Sleep Loss Reduces the DNA-Binding of BMAL1, CLOCK, and NPAS2 to Specific Clock Genes in the Mouse Cerebral Cortex

Mongrain, Valérie; Spada, Francesco La; Curie, Thomas; Franken, Paul

doi:10.1371/journal.pone.0026622

Cited by 105 publications

(80 citation statements)

References 74 publications

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“…4C), showing a peak at ZT6 and a trough around dark-light transition (ZT18-ZT0). This phase is similar to what we recently observed for binding to several clock genes (41). Furthermore, and also similar to our previous data (41), we found that SD decreases the binding of those transcription factors to the Nlg1 E-box (Fig.…”

Section: Resultssupporting

confidence: 92%

“…These last two observations parallel changes in the expression of Nlg1 with B, which provide support for a transcriptional control of Nlg1 with insert B by clock transcription factors. Thus, during enforced wakefulness, prolonged high neuronal activity could decrease CLOCK/BMAL1 binding to Nlg1 Eboxes as it does for other CLOCK/BMAL1 targets (41). This would lead to reduced expression of Nlg1 with B and NLG1 at the synapse and consequently to impaired NMDAR function (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…4 C and D) were from ref. 41 qPCR and Western Blotting. RNA extraction, reverse transcription, and qPCR experiments and analysis were performed as detailed before (9,35,52).…”

Section: Methodsmentioning

confidence: 99%

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Neuroligin-1 links neuronal activity to sleep-wake regulation

Helou

Bélanger-Nelson

Freyburger

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

104

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Maintaining wakefulness is associated with a progressive increase in the need for sleep. This phenomenon has been linked to changes in synaptic function. The synaptic adhesion molecule Neuroligin-1 (NLG1) controls the activity and synaptic localization of N-methyl-Daspartate receptors, which activity is impaired by prolonged wakefulness. We here highlight that this pathway may underlie both the adverse effects of sleep loss on cognition and the subsequent changes in cortical synchrony. We found that the expression of specific Nlg1 transcript variants is changed by sleep deprivation in three mouse strains. These observations were associated with strainspecific changes in synaptic NLG1 protein content. Importantly, we showed that Nlg1 knockout mice are not able to sustain wakefulness and spend more time in nonrapid eye movement sleep than wild-type mice. These changes occurred with modifications in waking quality as exemplified by low theta/alpha activity during wakefulness and poor preference for social novelty, as well as altered delta synchrony during sleep. Finally, we identified a transcriptional pathway that could underlie the sleep/wake-dependent changes in Nlg1 expression and that involves clock transcription factors. We thus suggest that NLG1 is an element that contributes to the coupling of neuronal activity to sleep/wake regulation.ChIP | EEG | gene expression | sleep homeostasis | synaptic plasticity S leep is crucial for learning, memory, and other functions essential for proper functioning of the brain and body (1, 2). These functions have been associated with the sleep recovery process, which defines a level of pressure for sleep that increases with wakefulness and dissipates during sleep and that is reflected by changes in sleep intensity (3, 4). Sleep intensity is indexed by electroencephalographic (EEG) markers of neuronal synchrony in delta frequencies (1-4 Hz) measured during nonrapid eye movement (NREM) sleep (5). During wakefulness, mechanisms favoring desynchrony in the delta range predominate, and the brain can maintain cognition, whereas during sleep, events promoting network synchrony mostly take place with high delta activity thought to be permissive of recovery (3, 6). The sleep recovery process has been hypothesized to originate and contribute to the maintenance of both synaptic and network equilibrium (6-8). This notion is supported by the observation that specific plasticityrelated genes may be directly involved in regulating sleep need (9). Certain clock genes may also directly contribute, in a circadian-independent manner, to the sleep recovery process (5, 9). However, the mechanisms underlying the capacity and requirement of the brain to switch from an alert desynchronized state to an unconscious synchronized state remain elusive.Glutamate, the main excitatory neurotransmitter of the brain, can induce long-term modifications of synaptic transmission and, thus, changes in network connectivity. This is achieved mainly via glutamate's action on two types of receptors: N-methyl-D-aspa...

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Neuroligin-1 links neuronal activity to sleep-wake regulation

Helou

Bélanger-Nelson

Freyburger

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

104

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show abstract

“…However, the levels and activity of Bmal1, Npas2, and Clock are intimately tied to circadian oscillation, and conditions that disrupt oscillation can suppress Bmal1 expression or transcriptional activity. These include cellular senescence, sleep deprivation, and pulsed-light exposure (44)(45)(46). Therefore, these circadian "stressors" may predispose individuals to age-related neurodegeneration by suppressing positive-limb clock gene expression and activity.…”

Section: Discussionmentioning

confidence: 99%

Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration

Musiek¹,

Lim²,

Yang³

et al. 2013

J. Clin. Invest.

414

448

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Brain aging is associated with diminished circadian clock output and decreased expression of the core clock proteins, which regulate many aspects of cellular biochemistry and metabolism. The genes encoding clock proteins are expressed throughout the brain, though it is unknown whether these proteins modulate brain homeostasis. We observed that deletion of circadian clock transcriptional activators aryl hydrocarbon receptor nuclear translocator-like (Bmal1) alone, or circadian locomotor output cycles kaput (Clock) in combination with neuronal PAS domain protein 2 (Npas2), induced severe age-dependent astrogliosis in the cortex and hippocampus. Mice lacking the clock gene repressors period circadian clock 1 (Per1) and period circadian clock 2 (Per2) had no observed astrogliosis. Bmal1 deletion caused the degeneration of synaptic terminals and impaired cortical functional connectivity, as well as neuronal oxidative damage and impaired expression of several redox defense genes. Targeted deletion of Bmal1 in neurons and glia caused similar neuropathology, despite the retention of intact circadian behavioral and sleep-wake rhythms. Reduction of Bmal1 expression promoted neuronal death in primary cultures and in mice treated with a chemical inducer of oxidative injury and striatal neurodegeneration. Our findings indicate that BMAL1 in a complex with CLOCK or NPAS2 regulates cerebral redox homeostasis and connects impaired clock gene function to neurodegeneration.

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“…Within this critical region, two TF motifs were identified: a consensus E-box motif (recognized by bHLH TFs) (Massari and Murre 2000), immediately next to a motif recognized by basic region leucine zipper (bZIP) proteins of the AP-1 family (Heinz et al 2010). Like neural bHLH proteins, AP-1 family proteins are known to have important roles in regulating gene expression in the cerebral cortex (Raivich and Behrens 2006;Mongrain et al 2011).…”

Section: Wwwgenomeorgmentioning

confidence: 99%

Massively parallel cis-regulatory analysis in the mammalian central nervous system

et al. 2015

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Cis-regulatory elements (CREs, e.g., promoters and enhancers) regulate gene expression, and variants within CREs can modulate disease risk. Next-generation sequencing has enabled the rapid generation of genomic data that predict the locations of CREs, but a bottleneck lies in functionally interpreting these data. To address this issue, massively parallel reporter assays (MPRAs) have emerged, in which barcoded reporter libraries are introduced into cells, and the resulting barcoded transcripts are quantified by next-generation sequencing. Thus far, MPRAs have been largely restricted to assaying short CREs in a limited repertoire of cultured cell types. Here, we present two advances that extend the biological relevance and applicability of MPRAs. First, we adapt exome capture technology to instead capture candidate CREs, thereby tiling across the targeted regions and markedly increasing the length of CREs that can be readily assayed. Second, we package the library into adeno-associated virus (AAV), thereby allowing delivery to target organs in vivo. As a proof of concept, we introduce a capture library of about 46,000 constructs, corresponding to roughly 3500 DNase I hypersensitive (DHS) sites, into the mouse retina by ex vivo plasmid electroporation and into the mouse cerebral cortex by in vivo AAV injection. We demonstrate tissue-specific cis-regulatory activity of DHSs and provide examples of high-resolution truncation mutation analysis for multiplex parsing of CREs. Our approach should enable massively parallel functional analysis of a wide range of CREs in any organ or species that can be infected by AAV, such as nonhuman primates and human stem cell-derived organoids.

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Sleep Loss Reduces the DNA-Binding of BMAL1, CLOCK, and NPAS2 to Specific Clock Genes in the Mouse Cerebral Cortex

Cited by 105 publications

References 74 publications

Neuroligin-1 links neuronal activity to sleep-wake regulation

Neuroligin-1 links neuronal activity to sleep-wake regulation

Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration

Massively parallel cis-regulatory analysis in the mammalian central nervous system

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